We have developed a new method to discover microbial causes of human disease, sequence-based computational subtraction. In this method, sequences from diseased tissue are compared to the human genome computationally, and the filtered sequences are highly enriched for non- human nucleic acids. I propose to apply computational subtraction to discovery viruses that cause human cutaneous T-cell lymphoma (CTCL). Specifically, we plan to generate cDNA libraries from CTCL biopsy specimens, to sequence a sampling of these libraries, and then to subtract the sequences computationally and experimentally against the human genome. Filtered sequences will be tested further for specific association with CTCL using the polymerase chain reaction. When we identify CTCL-associated sequences, we will then attempt to generate molecular clones of the entire putative viruses and begin to characterize the protein products of their genomes.